Tissue Binding of Drugs (Tissue Localization of Drugs)

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Chapter: Biopharmaceutics and Pharmacokinetics : Protein Binding of Drugs

The body tissues, apart from HSA, comprise 40% of the body weight which is 100 times that of HSA. Hence, tissue-drug binding is much more significant than thought to be.


The body tissues, apart from HSA, comprise 40% of the body weight which is 100 times that of HSA. Hence, tissue-drug binding is much more significant than thought to be.

A drug can bind to one or more of the several tissue components. Tissue-drug binding is important in distribution from two viewpoints:

1. It increases the apparent volume of distribution of drugs in contrast to plasma protein binding which decreases it. This is because the parameter is related to the ratio of amount of drug in the body to the plasma concentration of free drug and the latter is decreased under conditions of extensive tissue binding of drugs.

2. Tissue-drug binding results in localization of a drug at a specific site in the body (with a subsequent increase in biological half-life). This is more so because a number of drugs bind irreversibly with the tissues (contrast to plasma protein-drug binding); for example, oxidation products of paracetamol, phenacetin, chloroform, carbon tetrachloride and bromobenzene bind covalently to hepatic tissues.

Factors influencing localization of drugs in tissues include lipophilicity and structural features of the drug, perfusion rate, pH differences, etc. Extensive tissue-drug binding suggests that a tissue can act as the storage site for drugs. Drugs that bind to both tissue and plasma components result in competition between drug binding sites.

For majority of drugs that bind to extravascular tissues, the order of binding is:

Liver > Kidney > Lung > Muscles

Several examples of extravascular tissue-drug binding are:

1. Liver: As stated earlier, epoxides of a number of halogenated hydrocarbons and paracetamol bind irreversibly to liver tissues resulting in hepatotoxicity.

2. Lungs: Basic drugs like imipramine, chlorpromazine and antihistamines accumulate in lungs.

3. Kidneys: Metallothionin, a protein present in kidneys, binds to heavy metals such as lead, mercury, and cadmium and results in their renal accumulation and toxicity.

4. Skin: Chloroquine and phenothiazines accumulate in skin by interacting with melanin.

5. Eyes: The retinal pigments of the eye also contain melanin. Binding of chloroquine and phenothiazines to it is responsible for retinopathy.

6. Hairs: Arsenicals, chloroquine and phenothiazines are reported to deposit in hair shafts.

7. Bones: Tetracycline is a well-known example of a drug that binds to bones and teeth. Administration of this antibiotic to infants or children during odontogenesis results in permanent brown-yellow discoloration of teeth. Lead is known to replace calcium from bones and cause their brittleness.

8. Fats: Lipophilic drugs such as thiopental and the pesticide DDT accumulate in adipose tissues by partitioning into it. However, high o/w partition coefficient is not the only criteria for adipose distribution of drugs since several highly lipophilic (more than thiopental) basic drugs like imipramine and chlorpromazine are not localized in fats. The poor perfusion of adipose could be the reason for such an ambiguity. Reports have stated that adipose localization of drugs is a result of binding competition between adipose and non-adipose tissues (lean tissues like muscles, skin and viscera) and not partitioning.

9. Nucleic Acids: Molecular components of cells such as DNA interact strongly with drugs like chloroquine and quinacrine resulting in distortion of its double helical structure.

Table 4.2 compares plasma protein-drug binding and tissue-drug binding.


Comparison Between Plasma Protein-Drug Binding and Tissue-Drug Binding

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